1. Field of the Invention
The present invention relates to novel compounds that are nitric oxide donors and have neprilysin-inhibition activity. The invention also relates to pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat diseases such as hypertension, heart failure, pulmonary hypertension, and renal disease.
2. State of the Art
Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is an endothelial membrane bound Zn2+ metallopeptidase found in many organs and tissues, including the brain, kidneys, lungs, gastrointestinal tract, heart, and the peripheral vasculature. NEP degrades and inactivates a number of endogenous peptides, such as enkephalins, circulating bradykinin, angiotensin peptides, and natriuretic peptides, the latter of which have several effects including, for example, vasodilation and natriuresis/diuresis, as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health.
Several new classes of NEP inhibitors are described in U.S. Patent Application Publication Nos. 2012/0157383 to Gendron et al. and 2012/0157386 to Smith et al, both filed on Dec. 14, 2011; U.S. Patent Application Publication Nos. 2012/0213806 to Fleury et al. and 2012/0213807 to Fleury et al., both filed on Feb. 16, 2012; and U.S. application Ser. No. 13/666,538 to Hughes et al. filed on Nov. 1, 2012.
Nitric oxide (NO) is also believed to play a role in cardiovascular health due to its role in several physiological processes. NO is produced by nitric oxide synthase (NOS), an enzyme that exists in three isoforms. NO produced by the endothelial NOS (type III) isoform has antithrombotic action. Cardiovascular disease remain a key area of therapeutic interest since the number of people having various forms of heart disease continues to rise. Thus, there remains a need for improved therapies in this area. It is expected that adding an NO-releasing moiety to these new classes of NEP inhibitors will enhance their properties, for example by increasing endogenous NO under physiological conditions.